U.S. Pat. No. 4,683,328 generally describes compounds of the formula. ##STR2##
Wherein R represents hydrogen, or lower alkenyl having 1 to 6 carbon atoms; R.sub.1 represents hydrogen, vinyl, or lower alkyl having 1 to 4 carbon atoms and the wavy line represents R or S stereochemistry; R.sub.2, R.sub.3, and R.sub.4 are hydrogen or lower alkyl having 1-4 carbon atoms or R.sub.2 and R.sub.3 together with carbon Y form a cycloalkenyl having 4-6 carbon atoms, or R.sub.3 or R.sub.4 together with carbons X and Y form a cycloalkenyl having 4 to 6 carbons. The compounds are disclosed as having cytoprotective activity and gastric antisecretory activity and can be useful in the inhibition of stomach lesions such as ulcers. The patent teaches that the compounds have a lower diarrhea side effect than other prostaglandin analogs commonly associated with antisecretory/cytoprotective activity.
While the tetraenyl compounds have exhibited good cytoprotective and antisecretory activities while minimizing the diarrheal side effect commonly associated with prostaglandin analogs, the tetraenyl compounds also exhibit a stability concern that lessens the importance of the compounds as potential commercial candidates for the treatment of stomach lesions or gastrointestinal lesions such as ulcers. Specifically, these compounds readily undergo allylic rearrangement and dehydration degration reactions under acidic conditions (see Collins, et al., J. Med. Chem. 33, 2784, (1990)).
It would be desirable to provide compounds which exhibit protective activity while exhibiting a stability profile that would make the compounds beneficial for the treatment of animals experiencing gastrointestinal lesions and in need of cytoprotective therapy. It would also be desirable that such compounds maintain the lessened diarrheal side effect such as that exhibited with the compounds disclosed in the above noted patent reference.